Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two glucose-regulated proteins, GRP78 and GRP94, are major constituents of the endoplasmic reticulum (ER) of mammalian cells. These proteins are synthesized constitutively in detectable amounts under normal growth conditions; they can also be induced under a variety of conditions of stress including glucose starvation and treatment with drugs that inhibit cellular glycosylation, with calcium ionophores or with amino-acid analogues. Unlike the closely-related heat shock protein (HSP) family, the GRPs are not induced significantly by high temperature. Recently, GRP78 has been identified as the immunoglobulin heavy chain binding protein (BiP) (ref. 5 and Y.K. et al., in preparation) which binds transiently to a variety of nascent, wild-type secretory and transmembrane proteins and permanently to malfolded proteins that accumulate within the ER. We have tested the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin (HA) in simian cells. Only malfolded HAs, whose transport from the ER is blocked, induced the synthesis of GRPs 78 and 94. Additional evidence is presented that malfolding per se, rather than abnormal glycosylation, is the proximal inducer of this family of stress proteins.
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PMID:The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. 335 47

The FKB2 gene of Saccharomyces cerevisiae encodes a homolog of mammalian FKBP-13, an FK506/rapamycin-binding protein that localizes to the lumen of the endoplasmic reticulum (ER). We have found that FKB2 mRNA levels increase in response to the accumulation of unfolded precursor proteins in the ER. FKB2 mRNA levels are elevated in cells blocked in N-glycosylation--i.e., in wild-type cells treated with tunicamycin and in the sec53-6 mutant grown at the nonpermissive temperature. Mutations that block other steps in secretion have no effect on FKB2 mRNA levels, indicating that increases in FKB2 mRNA are not the consequence of a general block in secretion. The increase in FKB2 mRNA in response to unfolded proteins in the ER is mediated through a 21-bp unfolded-protein response (UPR) element located in the 5' noncoding region of FKB2. UPR elements present in other ER chaperone genes, such as yeast KAR2 (BiP), mammalian GRP78 (BiP), and GRP94, function in an analogous manner to that in FKB2. As with KAR2, FKB2 mRNA levels are also elevated by heat shock. The similarities in the regulation of FKB2 and other ER chaperone genes suggest that FKBP-13 may play a role in protein trafficking in the ER.
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PMID:The FKB2 gene of Saccharomyces cerevisiae, encoding the immunosuppressant-binding protein FKBP-13, is regulated in response to accumulation of unfolded proteins in the endoplasmic reticulum. 768 4

Current advances in human gene therapy open up new frontiers for molecular therapies of cancer. However, one major limitation in cancer gene therapy is the lack of a general tumor-specific promoter which allows stringent and high level expression of the therapeutic reagent in malignantly transformed but not normal tissues. Hallmark features of solid tumors such as glucose deprivation, chronic anoxia, and acidic pH induce the glucose-regulated proteins, in particular, GRP78/BiP, a M(r) 78,000 endoplasmic reticulum-localized protein with chaperone and calcium-binding properties. We report here that a truncated rat grp78 promoter with most of the distal basal elements removed can be utilized as a potent internal promoter in a retroviral vector to drive high level expression of a reporter gene in a murine fibrosarcoma model system. The stress-inducible grp78 promoter offers a novel approach for gene delivery systems targeting transcription in tumorigenic cells.
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PMID:Use of the stress-inducible grp78/BiP promoter in targeting high level gene expression in fibrosarcoma in vivo. 771 71

IgM antibodies are secreted as multisubunit polymers that consist of as many as three discrete polypeptides: mu heavy chains, light (L) chains, and joining (J) chains. We wished to determine whether L chains that are required to confer secretory competence on immunoglobulin molecules must be present for IgM to polymerize--that is, for intersubunit disulfide bonds to form between mu chains. Using a L-chain-loss variant of an IgM-secreting hybridoma, we demonstrated that mu chains were efficiently polymerized independent of L chains, in a manner similar to that observed for conventional microL complexes, and that the mu polymers incorporated J chain. These mu polymers were not secreted but remained associated with the endoplasmic reticulum-resident chaperone BiP (GRP78). This finding is consistent with the endoplasmic reticulum being the subcellular site of IgM polymerization. We conclude that mu chain alone has the potential to direct the polymerization of secreted IgM, a process necessary but not sufficient for IgM to attain secretory competence.
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PMID:Roles of heavy and light chains in IgM polymerization. 776 23

To determine the functional significance of endoplasmic reticulum chaperones in hematopoietic cells, we analyzed the expression and post-translational modification of BiP/GRP78 and GRP94 as well as the cytoplasmic chaperones HSP70 and HSC70 during the differentiation of a mouse myeloid leukemia cell line, M1. The amounts of BiP/GRP78 and GRP94 increased several-fold when M1 cells were induced to differentiate into macrophage-like cells by treatment with interleukin-6 (IL-6). Synthesis began to increase at 4 hr after IL-6 treatment. The phosphorylated form of BiP/GRP78 increased during the later stages of differentiation. These data suggested that the chaperone activity of BiP/GRP78 and GRP94 may be needed for differentiated macrophage-like cells or for the differentiation event itself, and that functionally different BiP/GRP78 accumulate during the differentiation of M1 cells.
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PMID:Expression and phosphorylation of BiP/GRP78, a molecular chaperone in the endoplasmic reticulum, during the differentiation of a mouse myeloblastic cell line. 779 66

Mammalian GRP78/BiP is a stress-inducible 78-kDa endoplasmic reticulum (ER) protein with molecular chaperone and calcium-binding properties. The transactivation of grp78 by the calcium ionophore A23187 provides a model system with which to study the signal transduction that allows mammalian cells to sense calcium depletion in intracellular stores and activate transcription of specific genes. Linker-scanning mutation analysis of the grp78 promoter reveals that the single most important regulatory element is C1, which contains a CCAAT motif most proximal to the TATA sequence. The C1 element is crucial for mediating the stimulatory effects by the upstream regulatory elements under normal and stress conditions. In this report, we establish that the heteromeric CCAAT-binding factor CBF is the major component of the C1-binding factor (C1F) in human cells. A GGAGG motif flanking the CCAAT sequence also contributes to high-affinity C1F/CBF binding. We show here that the binding of C1F in vitro is sensitive to the concentration of calcium ions. At high calcium ion concentrations, the C1F-binding activity is lower because of a higher dissociation rate. This binding characteristic correlates with the induction of grp78 transcription in response to the depletion of intracellular calcium stores. The strikingly similar behavior of C1F from nuclear extracts of control and A23187-treated cells further suggests that C1F itself does not undergo any major inherent changes after calium depletion stress. Rather, its binding property could be modulated by the immediate calcium ionic environment in stressed and nonstressed cells. On the basis of the in vitro and in vivo site occupancies of C1F and other stress-inducible changes of upstream regulatory complexes, we present a model to explain how C1F and other upstream factors can synergistically activate grp78 transcription in calcium-depleted cells.
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PMID:Transduction of calcium stress through interaction of the human transcription factor CBF with the proximal CCAAT regulatory element of the grp78/BiP promoter. 789 20

Starvation of mouse hepatoma cells for essential amino acids or glucose results in the ADP-ribosylation of the molecular chaperone BiP/GRP78. Addition of the missing nutrient to the medium reverses the reaction. The signal mediating the response to environmental nutrients involves the translational efficiency. An inhibitor of proteins synthesis, cycloheximide, or reduced temperature, both of which reduce translational efficiency, stimulate the ADP-ribosylation of BiP/GRP78. Inhibition of N-linked glycosylation of proteins results in the overproduction of BiP/GRP78. The over produced protein is not ADP-ribosylated suggesting that this is the functional form of BiP/GRP78. The over produced BiP/GRP78 can, however, be ADP-ribosylated if the cells are starved for an essential amino acid. BiP/GRP78 resides in the lumen of the endoplasmic reticulum where it participates in the assembly of secretory and integral membrane proteins. ADP-ribosylation of BiP/GRP78 during starvation is probably part of a nutritional stress response which conserves limited nutrients by slowing flow through the secretory pathway.
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PMID:ADP-ribosylation of the molecular chaperone GRP78/BiP. 789 57

During their transit through the endoplasmic reticulum, newly synthesized light and heavy chains of immunoglobulins associate with two endoplasmic reticulum stress proteins. BiP/GRP78, a member of the HSP70 family, binds these polypeptides, presumably through promiscuously exposed hydrophobic sequences, soon after their translocation into the endoplasmic reticulum. GRP94, another endoplasmic reticulum stress protein homologous to HSP90, also associates with unassembled immunoglobulin chains, but its interaction is biochemically, kinetically and structurally distinct from BiP's. We report here that whereas BiP preferentially binds an early disulphide intermediate of light chain and dissociates within a few minutes, GRP94 exclusively binds fully oxidized molecules and dissociates with a half-time of 50 min. These results indicate that GRP94 is itself a chaperone which acts after BiP.
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PMID:Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum. 791 87

The synthesis of complex biological structures such as antibodies using recombinant DNA technology is a major biotechnological advance. Active murine antibody (IgG) oligomers, composed of two heavy (H) and two light (L) polypeptide chains, have been expressed and secreted by the baculovirus-insect cell expression system. Unfortunately, expression of the functional antibodies is accompanied by the formation of abnormal protein complexes and aggregates in which the polypeptide chains are bound together into incorrect associations. The formation of these abnormal complexes or protein aggregates in insect cells may be caused by insufficient intracellular levels of two catalytic proteins, immunoglobulin binding protein (BiP or GRP78), and protein disulfide isomerase (PDI). Consequently, we obtained the genes coding for murine BiP and PDI and cloned the genes into the baculovirus vector (Autographa californica nuclear polyhedrosis virus) to obtain AcBB-BiP and AcBB-PDI. Infection of Spodoptera frugiperda (Sf-9) insect cells with these two baculoviruses yielded recombinant proteins of the correct size that were recognized by antibodies to these proteins. Cloning these genes into the baculovirus vector is one approach to engineering the assembly pathway in order to lower aggregation and increase production of functionally active proteins and oligomers.
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PMID:Engineering the assembly pathway of the baculovirus-insect cell expression system. 801 Jun 71

BiP/GRP78 is a member of the HSP70 family involved in the folding and assembly of proteins in the endoplasmic reticulum. Using PCR amplification of DNA from human x rodent somatic hybrids that segregate human chromosomes in conjunction with fluorescence in situ hybridization, we have assigned GRP78 to chromosome 9q34. This is in agreement with the localization of murine and bovine homologues based on the high degree of synteny in this region. Several interesting genes and disorders map to this region and are discussed.
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PMID:Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34. 802 Sep 77


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